A Combined Therapeutic Regimen of Buspirone and Environmental Enrichment is more Efficacrious than Either Alone in Enhancing Spatial Learning in Brain-Injured Rats

Abstract Buspirone, a 5-HT1A receptor agonist, and environmental enrichment (EE) enhance cognition and reduce histopathology after traumatic brain injury (TBI) in adult rats, but have not been fully evaluated after pediatric TBI, which is the leading cause of death in children. Hence, the aims of this study were to assess the efficacy of buspirone alone (Experiment 1) and in combination with EE (Experiment 2) in TBI postnatal day-17 male rats. The hypothesis was that both therapies would confer cognitive and histological benefits when provided singly, but their combination would be more efficacious. Anesthetized rats received a cortical impact or sham injury and then were randomly assigned to receive intraperitoneal injections ofbuspirone (0.08 mg/kg, 0.1 mg/kg, and 0.3 mg/kg) or saline vehicle (1.0 mL/kg) 24 h after surgery and once daily for 16 days (Experiment 1). Spatial learning and memory were assessed using the Morris water maze (MWM) on post-operative days 11-16, and cortical lesion volume was quantified on day 17. Sham controls for each condition were significantly better than all TBI groups. In the TBI groups, buspirone (0.1 mg/kg) enhanced MWM performance versus vehicle and buspirone (0.08 mg/kg and 0.3 mg/kg) (p\u3c0.05) and reduced lesion volume relative to vehicle (p=0.038). In Experiment 2, buspirone (0.1 mg/kg) or vehicle was combined with EE after TBI, and the data were compared to the standard (STD)-housed groups from Experiment 1. EE lead to a significant enhancement of spatial learning and a reduction in lesion size versus STD. Moreover, the combined treatment group (buspirone+EE) performed markedly better than the buspirone+STD and vehicle+EE groups, which suggests an additive effect and supports the hypothesis. The data replicate previous studies assessing these therapies in adult rats. These novel findings may have important rehabilitation-relevant implications for clinical pediatric TBI

Hair cortisol as a novel biomarker of HPA suppression by inhaled corticosteroids in children

Background: Asthma is the most common chronic condition in childhood, and the recommended pharmacotherapy for long-term control includes the use of inhaled corticosteroids (ICS). ICS were designed to act at the site of inflammation in the lung, thus decreasing systemic absorption and reducing the risk of adverse effects associated with corticosteroid use (e.g., HPA suppression and its consequent effects). Available data show that measurement of hair cortisol successfully reflects endogenous cortisol levels. We sought to examine whether hair cortisol measurements can be used to identify HPA suppression surrounding ICS therapy in children with asthma.Methods:Hair samples were collected from the vertex posterior region of the head of 18 asthmatic children. We compared their hair cortisol concentration during ICS use with the concentration prior to ICS use.Results:During ICS therapy, median hair cortisol levels were twofold lower compared with the period of no ICS use (median 89.8 ng/g vs. 198.2 ng/g, P = 0.0015).Conclusion:Hair cortisol is an effective biomarker of the HPA suppression associated with ICS therapy and can be a sensitive tool for determining systemic effects of ICS use and monitoring adherence. Future research is needed to characterize the effect of untreated asthma on hair cortisol concentrations, if any

Brief Report: HIV-1 gp120 T-Cell Responses Correspond to Infection Outcomes in the Global iPrEx Chemoprophylaxis Trial.

Association of HIV-1-specific T-cell responses to infection risk in seronegative individuals is controversial. We quantified and phenotypically characterized gp120-specific T-cell responses in HIV-1 exposed, but uninfected subjects enrolled in the global Pre-exposure Prophylaxis Initiative (iPrEx) chemoprophylaxis trial. IFNγ ELISpot responses were detected in 24% of subjects irrespective of infection outcome. HIV-1 gp120 envelope-specific T-cell responses were more uniformly IFN-γ+TNF-α+Mip-1β+ in persistently seronegative subjects relative to subjects who later seroconverted (median frequency of 76.5% and 66.5%, respectively). IFNγ responses targeted the V2 loop for subjects who remained seronegative. HIV-1 gp120 envelope V2 loop-specific CD8 T-cell responses may help to protect against HIV-1 acquisition

Clinical Practice Recommendations on Genetic Testing of CYP2C9 and VKORC1 Variants in Warfarin Therapy

Objective: To systematically review evidence on genetic variants influencing outcomes during warfarin therapy and provide practice recommendations addressing the key questions: (1) Should genetic testing be performed in patients with an indication for warfarin therapy to improve achievement of stable anticoagulation and reduce adverse effects? (2) Are there subgroups of patients who may benefit more from genetic testing compared with others? (3) How should patients with an indication for warfarin therapy be managed based on their genetic test results? Methods: A systematic literature search was performed for VKORC1 and CYP2C9 and their association with warfarin therapy. Evidence was critically appraised, and clinical practice recommendations were developed based on expert group consensus. Results: Testing of VKORC1 (-1639G\u3eA), CYP2C92, and CYP2C93 should be considered for all patients, including pediatric patients, within the first 2 weeks of therapy or after a bleeding event. Testing for CYP2C95, 6, 8, or 11 and CYP4F2 (V433M) is currently not recommended. Testing should also be considered for all patients who are at increased risk of bleeding complications, who consistently show out-of-range international normalized ratios, or suffer adverse events while receiving warfarin. Genotyping results should be interpreted using a pharmacogenetic dosing algorithm to estimate the required dose. Significance: This review provides the latest update on genetic markers for warfarin therapy, clinical practice recommendations as a basis for informed decision making regarding the use of genotype-guided dosing in patients with an indication for warfarin therapy, and identifies knowledge gaps to guide future research.

Sub-second periodicity in a fast radio burst

Fast radio bursts (FRBs) are millisecond-duration flashes of radio waves that are visible at distances of billions of light-years. The nature of their progenitors and their emission mechanism remain open astrophysical questions. Here we report the detection of the multi-component FRB 20191221A and the identification of a periodic separation of 216.8(1) ms between its components with a significance of 6.5 sigmas. The long (~3 s) duration and nine or more components forming the pulse profile make this source an outlier in the FRB population. Such short periodicity provides strong evidence for a neutron-star origin of the event. Moreover, our detection favours emission arising from the neutron-star magnetosphere, as opposed to emission regions located further away from the star, as predicted by some models.Comment: Updated to conform to the accepted versio